WO2006054288A1 - Polymeric nano-shells - Google Patents
Polymeric nano-shells Download PDFInfo
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- WO2006054288A1 WO2006054288A1 PCT/IL2005/001203 IL2005001203W WO2006054288A1 WO 2006054288 A1 WO2006054288 A1 WO 2006054288A1 IL 2005001203 W IL2005001203 W IL 2005001203W WO 2006054288 A1 WO2006054288 A1 WO 2006054288A1
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- Prior art keywords
- nano
- polymer
- shells
- shell
- structures
- Prior art date
Links
- 239000002078 nanoshell Substances 0.000 title claims abstract description 125
- 229920000642 polymer Polymers 0.000 claims abstract description 79
- 238000000034 method Methods 0.000 claims abstract description 53
- 238000004132 cross linking Methods 0.000 claims abstract description 35
- 239000002086 nanomaterial Substances 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 22
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- 230000014759 maintenance of location Effects 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 230000002000 scavenging effect Effects 0.000 claims abstract description 5
- -1 poly(propylene oxide) Polymers 0.000 claims description 30
- 239000000693 micelle Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 15
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- 239000000203 mixture Substances 0.000 claims description 12
- 230000002441 reversible effect Effects 0.000 claims description 12
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- 229920000463 Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) Polymers 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
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- 229920001451 polypropylene glycol Polymers 0.000 claims description 7
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- 239000003814 drug Substances 0.000 claims description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 229920000208 temperature-responsive polymer Polymers 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 3
- 229920001610 polycaprolactone Polymers 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
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- 239000000839 emulsion Substances 0.000 claims description 2
- 230000009931 harmful effect Effects 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- 230000000116 mitigating effect Effects 0.000 claims description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical group O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
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- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical class CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims 1
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- 108010038807 Oligopeptides Proteins 0.000 claims 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
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- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 7
- 238000012377 drug delivery Methods 0.000 description 7
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- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 description 6
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- 238000002360 preparation method Methods 0.000 description 6
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- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 3
- 239000012935 ammoniumperoxodisulfate Substances 0.000 description 3
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- 239000011258 core-shell material Substances 0.000 description 3
- JQZRVMZHTADUSY-UHFFFAOYSA-L di(octanoyloxy)tin Chemical compound [Sn+2].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O JQZRVMZHTADUSY-UHFFFAOYSA-L 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000003891 ferrous sulphate Nutrition 0.000 description 3
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- 230000003993 interaction Effects 0.000 description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- RBQRWNWVPQDTJJ-UHFFFAOYSA-N methacryloyloxyethyl isocyanate Chemical compound CC(=C)C(=O)OCCN=C=O RBQRWNWVPQDTJJ-UHFFFAOYSA-N 0.000 description 3
- XZZXKVYTWCYOQX-UHFFFAOYSA-J octanoate;tin(4+) Chemical compound [Sn+4].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O XZZXKVYTWCYOQX-UHFFFAOYSA-J 0.000 description 3
- 229920003213 poly(N-isopropyl acrylamide) Polymers 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NIMFJURSROYUGR-UHFFFAOYSA-N 2,2-diisocyanatoethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC(N=C=O)N=C=O NIMFJURSROYUGR-UHFFFAOYSA-N 0.000 description 2
- 241001397104 Dima Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- 239000002211 L-ascorbic acid Substances 0.000 description 2
- 235000000069 L-ascorbic acid Nutrition 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 2
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
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- 229920002057 Pluronic® P 103 Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
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- 238000000113 differential scanning calorimetry Methods 0.000 description 1
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- 239000002808 molecular sieve Substances 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- ZJDNTSGQAOAXNR-UHFFFAOYSA-N n-ethenyl-2-methylpropanamide Chemical group CC(C)C(=O)NC=C ZJDNTSGQAOAXNR-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
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- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920003224 poly(trimethylene oxide) Polymers 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- UAXOELSVPTZZQG-UHFFFAOYSA-N trimethyl acrylic acid Chemical compound CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
Definitions
- the present invention relates to polymeric nano-structures based on amphiphilic polymers, which structures are substantially hollow and respond to a temperature change by changing their volume.
- Smart polymers are an advanced class of materials tailored to display substantial property changes as a response to minor chemical, physical or biological stimuli, such as temperature, pH, biochemical agents, mechanical stresses, and electrical fields.
- Environmentally responsive polymers have attracted special attention over the last decade due to both their complexity and versatility, as well as to their application in various areas.
- the term "thermo- responsive” refers to the ability of a polymeric system to achieve significant chemical, mechanical or physical changes due to small temperature differentials.
- Reverse thermo.-responsive polymers exhibit a sharp viscosity increase with temperature within a narrow temperature interval, reversibly producing a gel from a low viscosity water solution. This endothermic phase transition takes place at a temperature called the Lower Critical Solution Temperature (LCST).
- LCST Lower Critical Solution Temperature
- thermo-responsive chains onto the surface of various nanoparticles, or blending said particles with a non-responsive matrix, may render the nano-particles responsive to temperature differentials.
- poly(N-isopropylacrylamide) or poly(N-vinylisobutyramide) chains were grafted onto polystyrene [Sakuma S. et al.: Adv. Drug Delivery Rev. 47 (2001) 21-37], and poly(N-isopropylacrylamide) was grafted onto polypeptide microcapsules [Kidchob T. et al.: J. Controlled ReI. 50 (1998) 205-14].
- a crosslinked core-shell microgel based on poly(N-isopropylacrylamide) was described, formed in a two
- PEO-PPO-PEO triblocks commercially available as PluronicsTM, have been investigated for drug solubilization and controlled release [Esposito E. et al.: Int. J. Pharm. 142 (1996) 9-23], for the prevention of post-surgical tissue adhesions [Steiner A. et al.: Obstetrics and Gynecology 77 (1991) 48-52], and in wound covering [Mohammed M. et al.: J. Periodontal Res. 33(6) (1998) 335-44.].
- the potential of thermo-responsiveness and related phenomena displayed by polymeric systems has not yet been fully utilized for the formation of discrete compartments applicable, e.g., in drug delivery. It is therefore an object of the invention to provide discrete nano-structures based on amphiphilic polymers.
- the invention relates to a method for manufacturing stable polymeric nano- structures (nano-shells), wherein said nano-structures are substantially hollow and respond to a temperature change by reversibly changing their volume, comprising the steps of: i) providing a polymer forming supramolecular structures when dispersed in a liquid environment; and ii) dispersing said polymer in a liquid environment to form said supramolecular structures and crosslinking said supramolecular structures, wherein said crosslinking occurs substantially within said structures, whereby said stable nano-shells are obtained.
- said polymer is an amphiphilic polymer which is dispersed in a liquid environment, and is crosslinked after forming supramolecular structures in said environment, which crosslinking stabilizes said structures and leads to the formation of said nano- shells.
- Said supramolecular structure is preferably a micelle, and said amphiphilic polymer is preferably a reverse thermo-responsive polymer.
- a method of the invention is preferably applied in an aqueous environment.
- Said polymer comprises preferably an amphiphilic copolymer comprising polyethylene oxide (PEO).
- Said polymer preferably comprises a hydrophobic segment, which may be selected, for example, from the group consisting of poly(propylene oxide) (PPO), ⁇ oly(tetramethylene oxide) (PTMO), poly(caprolactone) (PCL), poly(lactic acid) (PLA), and combinations thereof.
- Said cross-linking in the method of the invention, comprises functionalizing said polymer with a moiety capable of forming covalent linkage/s under conditions in which said supramolecular structures are not disrupted.
- a method for manufacturing said polymericic nano-shell comprises the addition reaction of vinyl group, such as, for example, vinyl group in a derivative of acrylic acid, etc.
- said cross-linking comprises a reaction of methacrylate. Said cross-linking is preferably achieved by involving methacrylate chains which are end-capped on said polymer.
- the invention further relates to a method for manufacturing a polymer nano- structure (nano-shell), wherein said nano-structure is substantially hollow and responds to a temperature change by changing its volume, comprising the step of i) providing a polymer comprising a PEO-(PPO)-PEO triblock; ii) end-capping said triblock with acrylate or methacrylate moiety; iii) mixing the end-capped polymer from step ii) in water at elevated temperature, thereby obtaining an emulsion comprising micelles; and iv) crosslinking said acrylate or methacrylate residues in said micelles, preferably in the presence of a catalyst, thereby obtaining said substantially hollow nano-shells.
- the crosslinking reaction can be performed by directly reacting the terminal end-groups of said polymer or by reacting said terminal end-groups with a crosslinking agent able of reacting with the reactive terminal groups.
- said reactive terminal groups may be methacrylate moieties that can then react with a crosslinking agent via a
- said reactive terminal groups may be the reactive end groups present in said polymer, for example the hydroxyl end groups of PEO-PPO-PEO polymers, and the crosslinking molecule may be any molecule able of reacting with said end groups under the conditions required.
- said crosslinking is mainly intramicellar.
- said nano-shells may be essentially spherical.
- the spherical nano-shells may be obtained when mixing the end-capped polymer at an elevated temperature that is below about
- Said nano-shells may be rod-like nano-particles. Such rod-like nano- structures are usually obtained when said mixing of the end-capped polymer occurs at an elevated temperature that is higher than about 65°. However, certain applications may require more complex structures, such as chains or nets of nano-shells. The invention enables to obtain more complex structures, for example by controlled, partially intermicellar, crosslinking. Said nano-shells may have a morphology of a chain of beads. In a preferred embodiment of the invention, the nano-shells comprise PEO-PPO-PEO dimethacrylate.
- the end-capped polymer has preferably a concentration of about 0.2% or less.
- the invention enables to obtain more complex structures, for example by blending more than one polymer.
- said polymers may display the transition at different temperatures, whereby said nano-shells will expand or shrink at different temperatures.
- the invention also enables to obtain more complex structures, for example, by blending more than one polymer able to generate micelles comprising chains of the different polymers.
- the different polymers preferably amphiphilic, may differ in their molecular weight.
- the polymer having a lower molecular weight may be end-capped with reactive groups, while the longer polymer may be end-capped with other segments performing other functions. Since the latter will protrude from the surface of the nano-shell formed by the shorter end- capped polymer, the protruding chains will be able to render the nano-shells with additional features by being able to develop specific interaction with their surroundings.
- the invention provides a polymer nano-construct (nano-shell) comprising a cross- linked supramolecular structure of a polymer, preferably an amphiphilic polymer. Said supramolecular structure is preferably a micelle.
- the nano-shell comprises a cross- linked supramolecular structure of a polymer, preferably an amphiphilic polymer. Said supramolecular structure is preferably a micelle.
- Said polymer preferably comprises PEO-PPO- PEO triblock.
- the triblock is end- capped with methacrylate moiety.
- the nano-shell of the invention responds to a temperature increase by decreasing its volume, and to a temperature decrease by increasing its volume. Said temperature change occurs preferably in a temperature interval of 25 to 45 °C, and still more preferably in a temperature interval of 28 to 40°C.
- Said nano-shell may change its volume by about two orders of magnitude.
- Said nano-shell may change its volume even by about three orders of magnitude, or more.
- a nano-shell according to the invention may be prepared so as to be biodegradable, for example by comprising lactoyl units or caprolactone units.
- the invention is also directed to a nano-shell as described above, for use in sequestering materials dispersed in a liquid environment.
- said material is a hydrophobic material, and said environment is an aqueous mixture.
- a nano-shell according to the invention may be used in such a manner that said sequestering may lead to concentrating said material, or to transporting said material, or to scavenging said material.
- Said material may be of a pharmaceutical or medical importance, e.g., being a medicament.
- a nano- shell according to the invention is preferably utilized as a drug delivery means.
- a nano-shell according to the invention may be also utilized for scavenging a medically or pharmaceutically undesired component, or for lowering the concentration of an undesired component, or for mitigating a harmful effect of such an undesired component.
- a nano-shell according to the invention may be
- a pharmaceutically or medically important substance in vivo which releasing may be associated with decreasing the volume of said nano- shell in response to a temperature increase.
- Fig. 1. demonstrates the temperature response of spherical shells
- Fig. 2. shows the stability of thermo-responsive properties of the spherical shells
- Fig. 3. presents spherical nano-shells at TEM
- Fig. 4. shows rod-like nano-shells at TEM
- Fig. 5. demonstrates the temperature response of rod-like nano-shells as
- Fig. 6. presents TEM micrographs of nano-shells produced under varying
- Fig. 7. presents DSC thermograms and X-ray diffraction patterns of F-127, F-
- Fig. 8. shows inter-micellar binding leading to the formation of nano-shell
- crosslinked micelles of an amphiphilic polymer possess very unique properties, forming nano-structures that are substantially hollow and which respond to a temperature change by changing their volume. It has further been found that a surprising level of sequestering of a hydrophobic component may be attained in an aqueous mixture comprising said nano-structures.
- nano-shells exhibit marked changes of size in response to temperature variations.
- the nano-shells were specifically obtained by dispersing a polymer comprising PEO-PPO-PEO triblock and PEO/PPO chain extended multiblocks end-capped with a methacrylate moiety.
- the invention also relates to essentially hollow polymeric nano-structures comprising PEO-PPO-PEO triblock and PEO/PPO chain extended multiblocks end-capped with a methacrylate moiety.
- the nano-structures of the invention are capable to sequester and to transport in their hydrophobic core components dispersed in aqueous environment, preferably hydrophobic components.
- the hollow nano-structures of the invention may have various shapes, and are distinctly responsive to the changes of temperature — substantially reducing their volume as the temperature rises, the effect being reversible. Where the term nano-structure is used, the inclusion of any polymeric particle is intended, having at least one dimension of the order of hundreds of nanometers or less.
- the invention further provides a method for preparing nano-sized essentially hollow structures (nano-shells) responding to a temperature change by changing its volume, comprising dissolving a polymer, preferably an amphiphilic polymer, in a liquid environment and forming a supramolecular structure of said polymer, followed by crosslinking said supramolecular structure, thereby affixing it and obtaining said nano-shells.
- a polymer preferably an amphiphilic polymer
- supramolecular structure is to be taken to mean, an assembly of polymer molecules that are bonded by non-covalent interactions (electrostatic, van der Waals, hydrophobic, entropic driven, and other interactions), wherein the dimensions of said assembly are not greater than, in order of the magnitude, micrometers.
- An amphiphilic polymer in the method of the invention preferably comprises PEO-PPO-PEO triblock end-capped with methacrylate.
- the nano-shells were obtained with various PEO-PPO-PEO triblocks, as well as various PEO/PPO copolymers, the basic features of the presently generated nano-shells are illustrated and exemplified with PEO99-PPO67-PEO99.
- This triblock known as F127, has a molecular weight of 12,600 and comprises 70 wt% PEO.
- the PEO-PPO- PEO dimethacrylate derivatives (F127-DMA) are obtained by the reaction of the native OH-terminated PEO-PPO-PEO triblock with methacryloyl chloride.
- F127-DMA forms micelles in an aqueous medium, they are crosslinked intra- micellarly using a known method, for example employing ascorbic acid, ferrous sulfate, and ammonium persulfate (APS) redox system [Sun et al.: Acta Biochimica et Biophysica Sinica 30(4), 407 (1998)].
- APS ammonium persulfate
- other than acrylate moieties may be used, such that the functionalized polymer preferably retains its original ability to generate the supramolecular structure.
- the functionalization of the triblock was followed by FTIR, which showed the gradual appearance of weak bands at 1713 cm- 1 and 1635 cm- 1 , corresponding to the carbonyl vibration of the ester group and to the vinyl double bond, respectively.
- 1 H-NMR analysis demonstrated the incorporation of methacryloyl groups, as revealed, for example, by the protons of the double bond appearing as duplets at 5.6 ppm and 6.2 ppm.
- the average-molecular weight and polydispersity were determined by GPC.
- the cross-linking of the hydrophilic PEO case not only stabilizes the micelles resulting in sturdy nano-constructs, but renders them also with a unique thermo-responsive behavior.
- the temperature-dependent dimensional response of these nano-structures is illustrated in Figure 1, which reveals a sharp transition, with the nano-shells shrinking dramatically (about 400 times by volume), as temperature rises between 25°C and 30°C .
- the TEM micrographs presented in Figure 3 show the spherical nano-structures formed.
- Figure 2 presents the reversible dimensional response of the micelles before and after being crosslinked, at 15°C and 40 0 C . The temperatures were chosen so as to be unquestionably below and above their respective transition values.
- F127 triblocks appear as molecular unimers at low temperatures and they form a micelle at a higher temperature.
- the size of F127 unimers is 6-7 nanometers, while the micelles attain a size of around 20 nanometers, at 40°C.
- the engineered nano-sized constructs decrease in size markedly when going from a lower temperature to a higher one, in a sharp and essentially reversible manner.
- the nano-shells formed exhibit a diameter of around 200 nanometers at 15°C, while displaying a markedly smaller size (approximately 40 nanometers) at 40 0 C.
- the behavior of the nano-shells disclosed hereby can also be exemplified by using PEO19-PPO54-PEO19 (P103). This triblock is shorter than F127 (MW 4950) and its unimers and micelles have a size of around 4 and 19 nm, respectively.
- Nano-shells built using P 103 displayed thermo-responsiveness, decreasing from their 850 nm expanded configuration at low temperature, down to 49 nm, above their transition.
- the striking ability displayed by these supramolecular assemblies to expand and contract reversibly, triggered by a temperature change, is an important feature of the nano-shells and renders them with unique properties, unattainable until now.
- the shape and size of micelles may depend on the temperature [Mortensen K. et al.: Macromolecules 28 (1995) 8829-34], and therefore, nano-shells having various geometries were "sculptured" by performing the cross-linking reaction at different temperatures.
- the outer case of the nano-shell and the core space in the cross-linked PEO-PPO- PEO nano-shells of the invention have their special roles. Since the very interface between these novel nano-constructs and the aqueous medium consists of PEO chains, these structures benefit also from the recognized enhanced biocompatibility of PEO chains. Furthermore, the ability of PEO segments to extend the blood circulation time by avoiding reticuloendothelial system uptake represents an additional beneficial feature of the nano-shells.
- the nano-structures of the invention are capable of binding hydrophobic materials in their cavities/lumens.
- the loading capacity of the nano-shells is illustrated here for Sudan III, a small hydrophobic molecule, as revealed by its uptake by rod-like nano-shells at different temperatures.
- Sudan III a small hydrophobic molecule
- the amount of Sudan III loaded was negligible. This behavior is attributed to the very large size of the core space, which fails to generate an environment able to solubilize this hydrophobic payload and, as a result, Sudan III precipitated out of the aqueous medium.
- the core space is much smaller, approximately 60% of the payload added to the water system (5 %wt) was actually loaded into
- nano-shells to incorporate large payloads is illustrated by comparing their behavior to that of F127 micelles, which were able to incorporate only around 35% of the payload.
- the nano-shells of the invention thus, provide a means for sequestering a component which is substantially insoluble in an aqueous mixture, and possibly concentrating it, or isolating, or transporting it.
- the nano-shells are used as a drug-delivery means. It is also worth
- the nano-shells of the invention do not suffer such drawbacks.
- the reactive double bonds present at the outer surface of the supramolecular structures can be used as anchoring sites for further derivatizations, using various synthetic pathways, comprising, e.g., free radical mechanism, Michael reaction, or other reactions known in the art.
- Said reactive double bonds can be used preferably during the synthesis of the nano-shells and even more preferably towards the end of the synthesis of the nano-shells, or once the synthesis has been substantially completed. For example, by adding amine-terminated chains at different stages of the process, inter-micellar binding was performed and additional constructs were formed.
- the surface reactivity of the nano- shells can be used to impart to them additional features, as exemplified by the end-capping of poly(acrylic acid) chains onto the periphery of these assemblies. It is understood that some applications will require quenching of any residual surface activity of the nano-shells, which may be achieved by the reactions known in the art.
- nano-shells are expected to be responsive not only to temperature, but also to pH. Furthermore, it is anticipated that the presence of the poly(acrylic acid) chains will render them mucoadhesive. By end-capping specific biological motifs, these nano-shells can also be of potential as vehicles for targeted drug delivery.
- the nano-shells were rendered biodegradable by binding short degradable segments, comprising, among others, lactoyl (LA) repeating units (up to 8) to each side of the triblock prior to the reaction with methacryloyl chloride to produce the respective methacrylates.
- LA lactoyl
- the presence of short LA blocks (2 and 4 lactoyl repeating units on each side) did not affect the behavior neither the size of the nano-shells, but the nano-shells became biodegradable. Even rather long blocks, consisting of 8 LA units on each side, produced constructs that retained their reverse thermo-responsiveness, but the assemblies tended to coalesce after 24 hours.
- Nano-shells based on other components were modified accordingly, following the same basic synthetic approach. The invention will be further described and illustrated in the following examples.
- the solvents used were of analytical grade and were dried adding molecular sieves 4A (BDH).
- Pluronic F127, Pluronic F103, tin octanoate, 2- isocyanatoethylmethacrylate and Sudan III were purchased from Sigma,
- methacryloyl chloride stannous octanoate and L-ascorbic acid from Aldrich, triethylamine (TEA) and ammonium peroxodisulfate from Riedel de-Haen, ferrous sulfate from Fluka, and lactide from Boehringer Ingelheim.
- Methacryloyl chloride was distilled before use.
- Nano-shells polymerization was achieved by dissolving 0.4 g of Fl27-diPLA-
- dimethacrylate in 200 ml of distilled water. The solution was heated to 5O 0 C for
- the characterization of the functional groups was carried out by FTIR analysis using a Nicolet Avatar 360 FTIR spectrometer.
- the samples were prepared by solvent casting from chloroform solutions, directly on sodium chloride crystals (Aldrich).
- the material was lyophilized with liquid nitrogen to remove water for 24 hours, and than subjected to a run were it was heated up from -2O 0 C to 100 0 C, at 5°C/min rate. The enthalpy of fusion was obtained from the area of the peak relative to the baseline.
Abstract
Description
Claims
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EP05807500A EP1819755A1 (en) | 2004-11-16 | 2005-11-15 | Polymeric nano-shells |
US11/719,247 US20090074819A1 (en) | 2004-11-16 | 2005-11-15 | Polymeric nano-shells |
IL183137A IL183137A0 (en) | 2004-11-16 | 2007-05-10 | Polymeric nano-shells |
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Cited By (5)
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WO2009061473A2 (en) * | 2007-11-07 | 2009-05-14 | Mallinckrodt Inc. | Photonic shell-core cross linked and functionalized nanostructures for biological applications |
JP2009173654A (en) * | 2008-01-22 | 2009-08-06 | Kwangju Inst Of Science & Technol | Temperature-sensitive nano-carrier |
US7638558B2 (en) | 2005-04-01 | 2009-12-29 | Intezyne Technologies, Inc. | Polymeric micelles for drug delivery |
US9295650B2 (en) | 2010-05-14 | 2016-03-29 | Mallinckrodt Llc | Functional, cross-linked nanostructures for tandem optical imaging and therapy |
WO2019211831A1 (en) * | 2018-05-01 | 2019-11-07 | Technion Research & Development Foundation Limited | Superabsorbent structure |
Families Citing this family (1)
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CN109575303B (en) * | 2018-12-03 | 2021-07-13 | 温州大学 | Amphiphilic polymer and preparation method thereof |
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- 2005-11-15 EP EP05807500A patent/EP1819755A1/en not_active Withdrawn
- 2005-11-15 US US11/719,247 patent/US20090074819A1/en not_active Abandoned
- 2005-11-15 WO PCT/IL2005/001203 patent/WO2006054288A1/en active Application Filing
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US8263665B2 (en) | 2005-04-01 | 2012-09-11 | Intezyne Technologies, Inc. | Polymeric micelles for drug delivery |
US8299128B2 (en) | 2005-04-01 | 2012-10-30 | Intezyne Technologies, Inc. | Compositions comprising polymeric micelles for drug delivery |
US8426477B1 (en) | 2005-04-01 | 2013-04-23 | Intezyne Technologies, Llc | Polymeric micelles for drug delivery |
US7638558B2 (en) | 2005-04-01 | 2009-12-29 | Intezyne Technologies, Inc. | Polymeric micelles for drug delivery |
US8779008B2 (en) | 2005-04-01 | 2014-07-15 | Intezyne Technologies, Inc. | Polymeric micelles for drug delivery |
US8263663B2 (en) | 2005-04-01 | 2012-09-11 | Intezyne Technologies, Inc. | Azide functionalized peptide targeting groups |
WO2009061473A2 (en) * | 2007-11-07 | 2009-05-14 | Mallinckrodt Inc. | Photonic shell-core cross linked and functionalized nanostructures for biological applications |
WO2009061473A3 (en) * | 2007-11-07 | 2009-11-05 | Mallinckrodt Inc. | Photonic shell-core cross linked and functionalized nanostructures for biological applications |
JP2009173654A (en) * | 2008-01-22 | 2009-08-06 | Kwangju Inst Of Science & Technol | Temperature-sensitive nano-carrier |
EP2082734A3 (en) * | 2008-01-22 | 2011-04-27 | Gwangju Institute of Science and Technology | Temperature-sensitive nano-carriers |
US9295650B2 (en) | 2010-05-14 | 2016-03-29 | Mallinckrodt Llc | Functional, cross-linked nanostructures for tandem optical imaging and therapy |
US9662387B2 (en) | 2010-05-14 | 2017-05-30 | Mallinckrodt Llc | Functional, cross-linked nanostructures for tandem optical imaging and therapy |
WO2019211831A1 (en) * | 2018-05-01 | 2019-11-07 | Technion Research & Development Foundation Limited | Superabsorbent structure |
US11718726B2 (en) | 2018-05-01 | 2023-08-08 | Technion Research & Development Foundation Limited | Superabsorbent structure |
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US20090074819A1 (en) | 2009-03-19 |
IL165260A0 (en) | 2005-12-18 |
EP1819755A1 (en) | 2007-08-22 |
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